Artesunate is a derivative of artemisinin, the active antimalarial component isolated from herb Artemisia annua (qinghaosu) in 1972, and synthesized by reacting dihydroartemisinin with succinic acid anhydride in basic medium (CN 85100781). Artesunate is widely used for the treatment of malaria, especially effective in the treatment of sever and multiple drug-resistant malaria. More importantly, artesunate is the only artemisinin analogue that can be administered intravenously and the World Health Organization (WHO) guidelines recommend intravenous artesunate as first line therapy for severe malaria (World Health Organization, Guidelines for the treatment of malaria; Second edition 2010). Moreover, recent studies have shown that artesunate has broad biological activities beyond antimalaria, ranging from anticancer, antivirus, treatment of inflammatory and immune diseases, and other parasite-related infections (e.g. schistosoma japonicum and toxoplasma) to antifungals (Ho et al, Pharmacol Ther, 2014, 142(1):126-139).
Liu describes artesunate for use in the treatment of malaria (Artesunate Research and Development, Lijiang Press, Jul. 1, 2010, 3-20). Efferth et al. report anticancer activity of artesunate against 55 cancer cell lines of the Departmental Therapeutics Program of the National Institutes of Health and cancer cells resistant to doxorubicin, vincristine, methotrexate and hydroxyurea (Int J Oncol, 2001, 18, 767-773). Ho et al. publish a comprehensive review on artemisinins in diseases conditions beyond malaria, including cancer, viral, fungal infection, other parasite infections, and inflammatory disorders (Pharmacol Ther, 2014, 142, (1):126-39). Yu et al. describe the treatment of lupus with artesunate (Chinese J Germ, 1997, 30, 51-53).
Sun et al. describe effect of artemisinin on ischemia/reperfusion injury of isolated rat myocardium (Zhongguo Zhong Yao Za Zhi, 2007, 32, 15:1547-51). Zhang et al. describe the use of artesunate in combination with a chemotherapy regimen of vinorelbine and cisplatin to treat patients with advanced non-small cell lung cancers (J Chin Integr Med, 2008, 6(2):134). Li et al. report use of artesunate for the treatment of sepsis model mice against heat-killed E. coli challenges (Int Immnopharmacol, 2008, 8, 379-389). Liu et al. describe artesunate for use in the treatment of severe malaria and sepsis or organ damage induced by malaria infections (J Trop Med, 2009, 9(7)755-756). WO2012168450 describes the ability of artesunate and its analogs to provide protection against organ injury caused by trauma haemorrhage and in stoke and burns injury, and to reduce the infarct size in myocardial infarction or to reduce the level of damage after the infarction has taken place. WO2014090306 describes artesunate for use in the treatment of acute, chronic kidney injury, uremia and in surgery that results in ischaemia-reperfusion (kidney transplantation, kidney and pancreas transplantation, coronary artery bypass graft).
Reid et al. describe the ability of artesunate to block left ventricular hypotrophy and improve cardiac function in adult mice subjected to transverse aortic constriction (J Mol Cell Cardiol, 2016, 97:106-13). Li et al. describe the use of artemisinin and its analogs to convert pancreatic α cells into β like cells through enhanced GABA signaling, restoring insulin production (Cell, 2017, 167, 1-15).
WO 2010/0137246 describes the use of artesunate in the treatment of asthma and respiratory distress syndrome. CN20151513816 describes artesunate for use in the treatment of idiopathic pulmonary fibrosis. Lai et al, describe the use of artesunate to alleviate hepatic fibrosis induced by multiple pathogenic factors (Eur J Pharmacol, 2015, 765, 234-241). All references described herein are incorporated by reference.
Artesunate is soluble in organic solvents, such as acetone and methanol, and slightly soluble in water. It becomes water soluble once formulated with 5% sodium bicarbonate solution and this formulation has been used in the clinic for more than 30 year as its only parenteral dosage form. Many studies have found that artesunate is unstable under basic and acidic conditions. It is also susceptible to degradation by moisture and heat (Agnihotri J. et al, J Pharmacy Res, 2013, 6:117-122). Therefore, artesunate injection has to be prepared immediately before use. The sodium bicarbonate formulation involves two-step preparation as instructed by the manufacturer (Guilin Pharmaceuticals, Guangxi, China). With a unit dosage of 60 mg, the first step is to dissolve artesunate by adding 0.6 mL or 1 mL of 5% sodium bicarbonate (2.3 equivalent or 3.8 equivalent, respectively) to artesunate powder and mixing vigorously for several minutes to have a clear solution, followed by the second step of dilution with 5.4 mL, or 5 mL, of 5% glucose or normal saline to the final concentration of 60 mg/6 mL. The dissolution produces significantly carbon dioxide bubbles upon the introduction of 5% sodium carbonate solution, reducing the contact of the drug powder with dissolution medium and thus lengthening the time needed for a complete dissolution. In addition, it is very difficult to determine whether artesunate is completely dissolved due to cloudiness caused by fizzing. This method is slow and complex. In this solution, artesunate starts to degrade within ten minutes and precipitation occurs within 2-3 hours (CN104414977). Therefore, a need exists for a new parenteral formulation, which should provide improved dissolution characteristics and enhanced stability of artesunate in aqueous solution.